1. Field of Invention
This invention relates to a novel esterification process. More specifically, this invention relates to a process for the direct esterification of a 17.alpha.-hydroxy group in a steroid bearing the dihydroxyacetone side chain.
In particular, this invention relates to a process for the direct esterification of a 17.alpha.-hydroxy group in a 3,20-dioxo-4-pregnene-17.alpha.,21-diol 21-hydrocarboncarboxylate by reaction thereof with an arylcarboxylic acid anhydride or halide and alkyl lithium at low temperatures whereby is obtained the corresponding 17.alpha.-arylcarboxylate. Said 17.alpha.-arylcarboxylates are useful as intermediates in preparing pharmacologically active steroids having anti-inflammatory activity.
2. Prior Art
In Breslow et al., U.S. Pat. No. 4,252,719 and in U.S. Pat. No. 4,260,464 are described the use of 17.alpha.-iodobenzoate esters of 9,11-unsubstituted steroids of the pregnane series to prepare the corresponding 9.alpha.-chloro derivatives useful as anti-inflammatory agents or as intermediates in the preparation of other anti-inflammatory steroids.
The prior art methods for preparing the requisite 17.alpha.-iodobenzene carboxylates described in U.S. Pat. Nos. 4,252,719 and 4,260,464 comprise reaction of the corresponding 17.alpha.-hydroxy steroid with an iodoaryl substituted reagent (preferably m-iodobenzoyl chloride) and an amine (e.g. pyridine or dimethylaminopyridine) in an organic solvent at elevated temperatures in an inert atmosphere.
This method, however, when applied to steroids having a dihydroxyacetone side chain, particularly to such steroids having a 16.beta.-methyl group, results in mixtures of products from which it is difficult to isolate the desired 17-ester.
By out invention, we have developed a novel method of directly converting a 17.alpha.-hydroxy group in a steroid of the pregnane series having a dihydroxyacetone side chain to the corresponding 17.alpha.-arylcarboxylate ester with minimal side reactions whereby is produced good yield of the 17.alpha.-arylcarboxylate ester substantially free by-products. Additionally, our esterification process advantageously is completed within a relatively short time as compared to prior art methods (e.g. in 4 hours, versus 22 hours for the U.S. Pat. No. 4,260,464 process). Our invention is particularly useful in preparing the 17.alpha.-iodocarboxylate ester of 16.beta.-methyl-1,4-pregnadiene-17.alpha.,21-diol-3,20-dione 21-benzoate, a valuable intermediate in the manufacture of betamethasone.